RESUMEN
PURPOSE: Preclinical studies have demonstrated that the adenovirus type 5 E1A gene is associated with antitumor activities by transcriptional repression of HER-2/neu and induction of apoptosis. Indeed, E1A gene therapy is known to induce regression of HER-2/neu-overexpressing breast and ovarian cancers in nude mice. Therefore, we evaluated the feasibility of intracavitary injection of E1A gene complexed with DC-Chol cationic liposome (DCC-E1A) in patients with both HER-2/neu-overexpressing and low HER-2/neu-expressing breast and ovarian cancers in a phase I clinical trial. PATIENTS AND METHODS: An E1A gene complexed with DCC-E1A cationic liposome was injected once a week into the thoracic or peritoneal cavity of 18 patients with advanced cancer of the breast (n = 6) or ovary (n = 12). RESULTS: E1A gene expression in tumor cells was detected by immunohistochemical staining and reverse transcriptase-polymerase chain reaction. This E1A gene expression was accompanied by HER-2/neu downregulation, increased apoptosis, and reduced proliferation. The most common treatment-related toxicities were fever, nausea, vomiting, and/or discomfort at the injection sites. CONCLUSION: These results argue for the feasibility of intracavitary DCC-E1A administration, provide a clear proof of preclinical concept, and warrant phase II trials to determine the antitumor activity of the E1A gene.
Asunto(s)
Proteínas E1A de Adenovirus/genética , Neoplasias de la Mama/terapia , Transferencia de Gen Horizontal , Terapia Genética , Neoplasias Ováricas/terapia , Adulto , Anciano , Apoptosis , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Colesterol/análogos & derivados , Citocinas/metabolismo , Femenino , Expresión Génica , Genes erbB-2 , Humanos , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Inyecciones , Antígeno Ki-67 , Liposomas , Persona de Mediana Edad , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Cavidad Peritoneal , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tórax , Células Tumorales CultivadasRESUMEN
Paclitaxel is a novel anticancer drug that is being increasingly used to treat cancer of the breast and other organs. We describe a patient with metastatic breast cancer and liver dysfunction who had severe mucocutaneous toxicity after administration of a standard dose of paclitaxel. Another interesting finding in this patient was that the administration of paclitaxel led to a prompt resolution of parathyroid hormone-related protein (PTHrP)-mediated hypercalcemia, which had previously proven to be refractory to multiple conventional antihypercalcemic agents as well as anthracycline-containing chemotherapy combination. The need for definitive guidelines for paclitaxel administration in the setting of hepatic dysfunction and the potentially unique sensitivity of PTHrP--producing cells to paclitaxel are discussed.